Treatment of parkinsonism in humans with nu, nu-diphenyl carbamates of alkylaminoalkanols



United States Patent O we Patemed seifijtiti R is ethylene. Thesecompounds can be synthesized by TREATMENT OF P IN HUMANS analogy to themethods known in the art, e.g., according WITH N,N DIPHENYL CARBAMATESOF German Patent ALKYLAMINOALKANOLS Typical examples of compoundsWhlCl'l may be utllrzed Gunther Stine, Bel-n, and Theodor Wagnel-Jam-egg5 in the method of treatment of the present invention are Zofingen,Switzerland, assignors to Siegfried Aktiengethe N9N-diPheHYICaTbamatES0f thfi followln'g alkylamlno' sellschaft, Zofingen, Switzerland, acorporation of alkanols:

Switzerland No Drawing. Continuation-impart of application Ser. No.2'dlmethylainmoethanol 183,356, Mar. 29, 1962. This application May 18,1965, l-dlethylammoethanol s ,45 ,g03 10 Z-methylethylammoethanol Claimspriority, application Switzerland, Mar. 29, 1961,Z-dipropylami-uoethanol 3,709/61 Z-ethylpropylaminoethanol 5 Clalms-2-dibutylaminoethanol 2-propylbutylaminoethanol3-diethylaminopropanol- 1) ABSTRACT OF THE DISCLOSURE 2dimethylaminopropanol-(l) The treatment of Parkinsonism in humans withN,N- Y {P 'P diphenyl carbamates of alkylaminoalkanols. l y P y P p3-d1methylam1no-propanol-(2) 3-diethylamino-propanol- (2) Thisapplication is a continuation-in-part of applicaf f tion Ser. No.183,356, filed Mar. 29, 1962, now aban- Y P li In addition to the abovecompounds there may be used Thls {m/entlon relates to a methPd oftreatlng Parkm each of the following carbamates of the above listedsonism in humans and more particularly relates to the alkylammoalkanols;

method of treatment of all types of Parkinsonism by administering to thepatient certain basic carbarnates or pharmaceutically acceptable saltsthereof.

It is known that certain substances with an atropinelike(anticholinergic) action can be used as remedies for treatingParkinsonism. For this purpose centrally acting anticholinergiccompounds are needed, which would be devoid as far as possible ofperipheral anticholinergic N- o-chlorophenyl) -N-phenylcarb amate N(3,4-dichlorophenyl) -N-phenylcarb am ate N,N-di- (o-chlorophenyl)eN-phenylcarb am ate :N- o-methylphenyl -N-phenylcarb am ate N-(p-chlorophenyl) -N-phenylcarb amate N,N-di-p-toly1carb am ate N-(m-methoxyphenyl) -N-phenylcarb am ate (erg. antispasmodic activity. Aclinically useful antiparkinson substance generally It probably neverwill be possible to find a substance inhibits tremors, produced in miceby a preliminary treatshowing either exclusively central or exclusivelyperiphent with tremorin, The antitremorin activity of our eral actions.As a matter of fact, preparations hitherto compounds has been comparedon tremorin treated mice used for the treatment of Parkinsonrsm alsoproduce side with the prior art antiparkinson drugs according to theeffects like inhibition f sahvation, mydriasis ge method of Everett et31., vide Science 124, 79 (1965). ment of the pupils) etc., caused bythe peripheral anti- Some of the results are given in the 'followingtable choliner gic components of their activity. (Table I):

TABLE I I II III 1V V Tremor-inhi- Mydriasis Drug LD50, bitiOll, EDaoLjD w EDm ED111111 EDm /EDm mg. kg., p.o. mg. kg. p.o. lug kg. 11.0.

Phen lntarimid 4 l, 200 17 70 10 0. 6 Biperidnn 4 545 9 61 1O 1. 1Trihexyphenidyl 4 365 13 2s 24 1. 8 Orphenadrin, i e 310 14, 5 21 35 2.4

1 Amount of substance in Lug kg. perorally administered necessary toproduce lethality determined by the method of Litchfield and Wilcoxon,J. Pharmacol. 96, 99 (1949).

2 For inhibition of tremor in 50% of mice treated with tremorin (averagedose).

3 The dose necessary for a pupil diameter increase of 10 scale units.

4 Values taken from Frommel and Fluery, J. Suisse Med 88, 713 (1958)made the discovery that there BXiStS a g p of It should be noted that acompound is considered to Substances with unexpected high Prevailingcentral be valuable for the treatment of tremor (Parkinsonism)anticholingeric action. This group of substances are carif it ED value il I th thi d l n (III) f bamates the general Structure! the table a highLD /ED figure indicates the combi- R1 4 nation of good antitremoractivity with low toxicity. In

\ 0 the fourth column a high figure indicates low mydriasis (undesiredside effect). In the fifth column a high figure is R2 an expression forhigh antitremor activity combined with wherein R and R are the same ordifierent groups sea low undesired side effect. Since for our compoundlected from the class consisting of phenyl, lower alkyl- SD-25 thisvalue (28) is more than ten times higher than phenyl, loweralkoxy-phenyl and halo-phenyl, R is lower the next best compound (2.4),it is obvious that SD-25 alkylene and R and R are the same or differentlower represents surprisingly favorable eliects. The comparison alkylgroups. In the preferred class of compounds R with orphenadrin furtherdemonstrates that in this field and R are phenyl, R and R are methyl orethyl and structural resemblance does not enable prediction of a 3specific kind of biological activity. Besides SD-25, its lowerhomologue, containing two methyl groups instead of the two ethyls ofSD-25, is a particularly effective antitremorine agent.

The compound SD-25 is known in the literature approximately since 50years and its local anesthetic effect and other pharamadocynamicproperties have been described. Sekera and Vrba (Arc. Int., Pharmacodyn,125, 316, 1960) state that their S-25 (identical with our SD-25)possesses 0.5-1 times the anticholinergic action of the well knownspasmolytic agent Trasentine. Trasentine is a mainly musculotropicallyacting, ie a papaverinelike antispasmodic; it is evaluated in generalagainst BaCI -induced spasms. Its peripheral anticholinergic action (asdetermined on the acetylcholine produced spasm of intestines) amountsonly to of the action of atropine (cf. L. Meier, Klin. Wochenschrift 39,1403 (1936)). Therefore the statement of Sekera and Vrba suggests thatthe anticholinergic activity of SD-25 on the rabbit ileum is only of theactivity of atropine. According to our own experiments of the effect ofSD-25 against acetylcholine induced spasms on the isolated guinea pigileum is even only that of atropine.

This, in addition to our observation of the low mydriatic effect ofSD-25 proves, that this substance has only a rather slight peripheralanticholinergic effect.

The central cholinergic activity of SD-25, as required for Parkinsonremedies and as demonstrated on tremorine treated rats, by us in thisapplication, never has been described before.

For obvious reasons, when isolating any of the compounds of Formula I inthe form of an acid addition salt, the acid is preferably selected so asto contain an anion which is non-toxic and pharmacologically acceptableat least in usual therapeutic doses. Representative acid addition saltsare hydrochlorides, hydrobromides, sulphates, phosphates, nitrates,acetates, lactates, maleates, citrates, tartrates and bitart-rates,succinates, oxalates, methanesulphonates and ethanesulphonates. Otheracid addition salts are likewise suitable and may be employed ifdesired.

Clinical trials with the hydrochloride of the N,N-diphenylcarbamate of2-diethylaminoethanol (SD-25) have proven the good therapeutic effectsof this substance concerning rigor and tremor, when administered topatients suffering from diseases of the extra pyramidal system, e.g.true Morbus Parkinson or parkinsonism of an arteriosclerotic orpostencephalitic origin. Furthermore it can be used for the treatment ofextrapyramidal symptoms, such as trismus, the tongue-gorge syndrom,spastic rigor and tremor, produced as undesired side effects, whenneuroleptics such as reserpin or phenothiazines, e.g. [gamm a- (N-methylpiperazino) -propyl] -phenothiazin- 2-sulfonic acid dimethylamide(thioperazin) are administered to patients (medicamental parkinsonism).SD- can be administered either together with the neuroleptic agent,afterwards or even before.

SD-25 is well tolerated and no deleterious effects have been observed,even when the drug was given for more than one year. The patients do notcomplain of dryness of the mouth or other side effects, which frequentlyare observed when other antiparkinson remedies are administered.

SD-25 can be given perorally and parenterally (intravenously orintramuscularly) in average doses of 15 to 50 mg., 2-4 times p.d. It ispossible to inject it i.v. re-

peatedly within a time interval of 15 to 30 minutes, whereby in certaincases particularly good therapeutic results have been obtained.

For injection purposes a 1-3%, preferably 2.5% aqueous solution,containing 25 mg. of SD-25 per ml. is generally used. For peroraltreatment for instance 24 tablets of 25 mg. SD-25 are given daily. Ofcourse, the optimal dose is individually different and can beascertained by the physician for singular cases.

It will be understood that the compositions used in the presentinvention can be brought into a unit dosage form by any suitabletechnique known to the man skilled in the art. A typical example of amethod to prepare tablets containing the preferred2-diethylaminoethyl-N-diphenylcarbamate will be given below: p I

Grams 2-diethylaminoethyl-N-diphenylcarbamate hydrochloride 25 Milksugar powder 50 Highly dispersed silicic acid (trademark Aerosil) 10Potato starch are intimately blended and then granulated. After additionof Grams Stearic acid powder 10 Powdered agar agar 10 Highly dispersedsilicic acid (Aerosil) 10 the so obtained mass is intimately mixed againand pressed into 1000 tablets containing each 25 mg. of the said activeingredient. Instead of the above carriers there can be used of courseany other suitable carriers such as talc, mannose, corn starch,magnesium stearate, etc.

We claim:

1. A method of treating parkinsonism in human comprising administeringto said humans afflicted with parkinsonism an effective amount of acompound selected from the group consisting of compounds having thefollowing formula and pharmaceutically acceptable acid addition saltsthereof wherein R and R are phenyl, R is lower alkylene and R and Rindependently are lower'alkyl.

2. A method according to claim 1, wherein R and R are independentlyselected from the group consisting of methyl and ethyl.

3. A method according to claim 2, wherein R is ethylene.

4. A method according to claim 3, wherein R and R are ethyl.

5. A method according to claim'4, wherein the compound is administered2-4 times per day in a dosage unit between about 15 and 50 mg. of thecompound.

References Cited Sekera et al.: Arch. Intern. de Pharm, et de Therapic,vol. 125, No. 3-4, pp. 311-319 (1960).

ALBERT T. MEYERS, Primary Examiner.

S. FRIEDMAN, Assistant Examiner.

